Melatonin is secreted exclusively at night. The duration of its secretion is proportional to the duration of night--longer in winter and shorter in summer. Animals use these seasonal changes in the duration of nocturnal melatonin secretion as a chemical signal to regulate the timing of seasonal changes in their behavior. Long nightly periods of secretion trigger winter-type behaviors, while short nightly periods of secretion trigger summer-type behaviors. In this project, we tested the hypothesis that lengthening of duration of nocturnal melatonin secretion in winter causes symptoms of winter depression in patients with seasonal affective disorder (SAD). In animals, the effect of night-length on the duration of melatonin secretion is mediated by a clearly defined neural circuit that originates in the retina and terminates in the pineal gland. The initial transduction of the light signal appears to be mediated by novel photoreceptor molecules in the retina. The timing of melatonin secretion is programmed by circadian pacemaker cells in the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives input from the retina and acts on the pineal via a multi-synaptic neural pathway. The SCN pacemaker contains two components, one that is synchronized with dusk and controls the evening onset of melatonin secretion and another that is synchronized with dawn and controls the morning offset of melatonin secretion. Downstream responses to changes in duration of nocturnal melatonin secretion are mediated by melatonin-receptors in the pars tuberalis of the pituitary gland and in the posterior hypothalamus. To test the hypothesis that changes in duration of nocturnal melatonin secretion cause winter depression, we measured blood levels of melatonin every 30 minutes for 24 hours in constant darkness on two occasions, once in winter and once in summer, in 55 patients and 55 healthy volunteers. Consistent with the hypothesis, we found that the duration of nocturnal melatonin secretion was longer in winter than in summer in patients with SAD, but not in healthy controls. This research is the first to detect an abnormality in patients with SAD in a system that is known to regulate seasonal behavior in animals. It points to a possible cause of winter depression, and it may explain why some individuals become depressed in winter while others do not.